Cancer of the prostate is one of the three leading causes of death in the adult male cancer patient. 30 percent of men over the age of 50 and 50 percent over 70 may have histologic carcinoma of the prostate. Yet little is known about its etiology. The specific aims are 1) to determine whether TPA (12-0-tetradecanoylphorbhol-13-acetate), a potent tumor-promoting agent, has promoting activity in human prostatic epithelium; and 2) to determine whether prolactin (P) and cadmium may act as promoting agents in human prostate carcinogenesis. We propose to test four hypotheses: 1) that TPA, a known tumor-promoting agent in other cell types, induces changes in prostatic epithelium, generally associated with promoting activity; 2) that prolactin, an intrinsic hormonal factor, acts as a tumor promoter in human prostate carcinogenesis; 3) that cadmium, an environmental pollutant, may act as an initiator or a promoter; and 4) that benzo(a)pyrene (BP), the most common polycyclic aromatic hydrocarbon in man's environment, may be an initiating agent and may induce tumors in association with P and Cd. The ability of TPA, P and Cd to induce elevated levels of plasminogen activator and ornithine decarboxylase, hyperplasia and inhibition of differentiation will be used as indicators of their promoting potential. The ability to induce such changes in cell function and behavior are generally associated with promoting activity. In vitro cell model systems of human prostatic origin, consisting of organ and epithelial cell cultures, co-cultivated epithelium and fibroblasts, and established human prostatic carcinoma cell lines will be used. Proposed studies are unique because we intend to use human cell model systems which are the ultimate test system for identifying agents involved in human cancer induction. Also we have elected to test the promoting activity of prolactin, a natural hormone whose levels increase in men after age 50. Cd and BP has been selected because a) they are common pollutants in man's environment; b) association of Cd with human prostatic carcinoma is suspected; c) BP is a known initiating agent in carcinogenesis in a variety of tissues in animal systems. Since biological effects of TPA are well characterized, these will serve as a background against which the effects of suspect agents (P and Cd) will be evaluated. These studies will make significant contributions in the areas of etiology and prevention of prostate cancer.